The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage. Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease (IBD). Oral administration is the most common route for intestinal diseases. In this study, a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment, which can interrupt the pathological process of IBD, resulting in the significantly improved efficacy of existing treatments. Based on the specific pH values and high reactive oxygen species (ROS) levels in inflammatory sites of IBD, an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed, and confirmed in vitro and in vivo. The anti-inflammatory drug dexamethasone acetate (Dex) and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions (TJs). The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis. In brief, a drug delivery system and a therapeutic strategy for IBD are successfully developed.